rs2499846

Variant names:

• chr1-161963258-G-A
• rs2499846
• NM_007348.4:c.*4604G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007348.4(ATF6):​c.*4604G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 152,148 control chromosomes in the GnomAD database, including 32,346 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (32346 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ATF6 NM_007348.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 6 publications found

Genes affected

ATF6 (HGNC:791): (activating transcription factor 6) This gene encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Although it is a transcription factor, this protein is unusual in that it is synthesized as a transmembrane protein that is embedded in the ER. It functions as an ER stress sensor/transducer, and following ER stress-induced proteolysis, it functions as a nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is present in the promoters of genes encoding ER chaperones. This protein has been identified as a survival factor for quiescent but not proliferative squamous carcinoma cells. There have been conflicting reports about the association of polymorphisms in this gene with diabetes in different populations, but another polymorphism has been associated with increased plasma cholesterol levels. This gene is also thought to be a potential therapeutic target for cystic fibrosis. [provided by RefSeq, Aug 2011]

ATF6 Gene-Disease associations (from GenCC):

• achromatopsia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• ATF6-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• achromatopsia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4	c.*4604G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000367942.4	NP_031374.2
ATF6	NM_001437597.1	c.*4604G>A		3_prime_UTR_variant	Exon 16 of 16		NP_001424526.1
ATF6	NM_001410890.1	c.*4604G>A		3_prime_UTR_variant	Exon 16 of 16		NP_001397819.1
ATF6	XM_011509309.1	c.*4604G>A		3_prime_UTR_variant	Exon 16 of 16		XP_011507611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4	c.*4604G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_007348.4	ENSP00000356919.3
ATF6	ENST00000681738.1	n.*56+4548G>A		intron_variant	Intron 16 of 16			ENSP00000505025.1
ATF6	ENST00000681801.1	n.*56+4548G>A		intron_variant	Intron 16 of 16			ENSP00000505998.1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96994 AN: 152030 Hom.: 32332 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.642

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.638 AC: 97042 AN: 152148 Hom.: 32346 Cov.: 33 AF XY: 0.636 AC XY: 47351 AN XY: 74396

African (AFR) AF: 0.471 AC: 19549 AN: 41480

American (AMR) AF: 0.536 AC: 8200 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2442 AN: 3464

East Asian (EAS) AF: 0.520 AC: 2687 AN: 5172

South Asian (SAS) AF: 0.589 AC: 2843 AN: 4824

European-Finnish (FIN) AF: 0.816 AC: 8661 AN: 10610

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50560 AN: 67986

Other (OTH) AF: 0.637 AC: 1346 AN: 2114

Alfa AF: 0.656 Hom.: 5877

Bravo AF: 0.609

Asia WGS AF: 0.518 AC: 1802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.24
DANN	Benign	0.42
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2499846; hg19: chr1-161933048;